It has been reported in the literature that therapeutically effective peptides (aan) with two or more amino acids (n≧2) are poorly absorbed orally. Even a peptide of as few as two amino acids, or related structures, exhibits very narrow absorption windows and poor bioavailability. As an example, the Physician's Desk Reference (PDR) reports that the angiotensin converting enzyme (ACE) inhibitor Enalaprilat (R1-Ala-Pro; n=2) is very poorly absorbed orally. Enalapril (R2-Ala-Pro), which is a pro-drug of Enalaprilat, is better absorbed orally, but the end result demonstrates only a 25% relative bioavailability of the active moiety (Enalaprilat) released from in vivo cleavage of the pro-drug. In comparison, Lisinopril (R3-Lys-Pro) has relatively good solubility in water, but only a moderate oral bioavailability (<25%), with a Tmax (time to maximum serum levels in vivo) of more than seven hours. Thus, this class of therapeutic species is preferably administered via a non-oral delivery method, such as by injection. However, even when delivered intravenously, the therapeutically active species has a relatively short serum half-life.
It is also known that some tri-peptides originating in food products may be capable of effective oral absorption, but to an unknown extent. However, no active tri- or longer peptide drug substances (n≧3) displaying oral absorption have been identified.
In accordance with the present invention compositions and methods providing for the oral absorption of peptide drug substances (aan) and other poorly orally absorbed drugs are disclosed. Furthermore, it has now been found that, through practice of the methods of the present invention, the length of the peptide drug entity (n) can be increased, particularly when the composition is administered parenterally, such as by intravenous (i.v.) administration, with the result of significantly improved pharmacological and therapeutic effects for the active drug moiety. Accordingly, through the practice of the present invention, it is possible to chemically modify a peptide species a pseudo-peptide or peptide mimic of known therapeutic utility to both permit the oral administration of the species and to drastically improve its pharmacological properties even when administered through a parenteral route. The invention also makes it possible to provide a cellular immune response in immunizing against agents such as viruses for which antibodies have been shown to enhance infectivity and in providing such a response against both chronic and latent viral infections and against malignant cells.
In the present disclosure, the word “peptide” corresponds to any sequence of naturally occurring amino acids, as well as to pseudo-peptides and to peptide mimics. By “pseudo-peptide,” is meant a chemical modification of one or more of the amino acid residues constituting the peptide or of their bonds such as, but not limited to, use of amino acids in their D-configuration, use of N-methyl amino acids, replacement of one or more peptidic bonds (—CO—NH) by a reduced bond (—CH2NH) and/or by —NHCO, —CH2CH2, —COCH2, —CHOHCH2 or —CH2O. By “peptide mimic,” is meant any amino acid sequence in which the —C— backbone has been replaced by an oligourea backbone or an oligocarbamate backbone. ω-Peptides are also included in this definition.
By “lipopeptides” is meant a combination of natural peptides (not involving any modified amino acids or modified bonds) and a lipid moiety;
By “lipopseudo-peptides” is meant pseudo-peptides coupled with a lipid moiety.
By “chemically modified amino acid aan” is meant an amino acid sequence wherein at least one of the amino acid residues in their bonds is modified as set forth above in these definitions.